The relatively homogenous clinical features and poor prognosis of chronic myelomonocytic leukemia (CMML) are associated with a molecular heterogeneity, with various mutations impacting several convergent pathways. Due to the restricted understanding of the mechanism involved in leukemogenesis, CMML still appears as a diagnostic and therapeutic undertaking, and poor prognosis of leukemia. Contrary to chronic myelogenous leukemia, BCR-ABL1-positive, cytogenetic, and molecular abnormalities of CMML are not specific and not pathognomonic, confirming the different levels of heterogeneity of this disease. Various mutations can be associated with a common phenotype not distinct at the clinical level, further demonstrating that molecular probings are needed for choosing individual targeted therapies.